Acute congenital Toxoplasma gondii infection alters fetal hematopoiesis via interferon-gamma

Abstract

Abstract In adulthood, infection drives cytokine-mediated inflammation that can directly influence hematopoietic stem and progenitor cell (HSPC) function and differentiation, but the effects of maternal infection on the trajectory of fetal hematopoietic and immune cells have not been elucidated. Toxoplasma gondii is a TORCH pathogen that can be vertically transmitted upon acute infection during pregnancy, with dire consequences for the developing fetus. Maternal IFNγ production during congenital infection is required to prevent vertical transmission and promote parasite clearance, but at the cost of lowered birth weights and premature abortion. Here, we investigated the effects of acute congenital toxoplasmosis on fetal hematopoiesis. Our examination of fetal hematopoiesis in response to maternal T. gondii infection of varying virulence revealed that discrete HSPC populations, including subsets of fetal hematopoietic stem cells, B1 precursors, and myeloid progenitors are fundamentally altered in response to congenital toxoplasmosis. To assess the ability of IFNγ to mediate these observed changes and directly cross the placental barrier, we performed epistatic crosses of mice deficient for IFNγ receptor. Our results indicate that maternal IFNy produced in response to T. gondii infection may drive observed changes to the fetal HSPC compartment and that fetal HSPCs respond directly to maternal sources of IFNγ in a manner distinct from adult HSPCs. Ongoing experiments attempt to resolve the mechanisms by which vertical transmission and maternal inflammation perturb the establishment of the fetal immune system, and the direct role of IFNγ in mediating these phenomena.